Practical Synthesis of Polyamine Succinamides and Branched Polyamines

Abstract Antibiotic resistance is now a growing threat to human health, further exacerbated by the lack of new antibiotics. We describe the practical synthesis of a series of substituted polyamine succinamides and branched polyamines that are potential new antibiotics against both Gram‐positive and Gram‐negative bacteria, including MRSA and Pseudomonas aeruginosa. They are prepared via 1,4‐Michael addition of acrylonitrile and then hydrogenation of the nitrile functional groups to primary amines. They are built upon the framework of the naturally occurring polyamines thermine (3.3.3, norspermine) and spermine (3.4.3), homo‐ and heterodimeric polyamine succinic amides. Linking two of the same or different polyamines together via amide bonds can be achieved by introducing a carboxylic acid group on the first polyamine, then coupling that released carboxylic acid to a free primary amine in the second polyamine. If the addition of positive charges on the amino groups along the polyamine chains are a key factor in their antimicrobial activity against Gram‐negative bacteria, then increasing them will increase the antimicrobial activity. Synthesising polyamine amide dimers will increase the total net positive charge compared to their monomers. The design and practical synthesis of such homo‐ and hetero‐dimers of linear polyamines, spermine and norspermine, are reported. Several of these compounds do not display significant antibacterial activity against Gram‐positive or Gram‐negative bacteria, including MRSA and Pseudomonas aeruginosa. However, the most charged analogue, a branched polyamine carrying eight positive charges at physiological pH, displays antibiofilm activity with a 50 % reduction in PAO1 at 16–32 μg mL−1.

3 to afford the fully protected polyamine 6. The trifluoroacetate protecting group was then removed by increasing the pH of the solution to above 11 with conc. aq. ammonia (32%) and then stirring at 20 ℃ for 18 h. The solution was concentrated under reduced pressure. The column chromatography was elution with DCM in MeOH (9.5:05 v/v). After combining fractions and concentrating them, the desired product 8 was obtained as a colourless oil (0.57 g, 46%). TLC analysis showed one spot (Rf =

Synthesis of compound 10
A solution of the tri-Boc protected spermine 8 (0.61 g, 1.21 mmol) in anhydrous pyridine (5 mL) under nitrogen was treated with succinic anhydride (0.12 g, 1.21 mmol, 1 equiv.) at 20 °C. The solution was stirred for a further 18 h. The solution was then concentrated in vacuo. The crude material was extracted with chloroform (3 x 15 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo. The desired product 10 was obtained as a colourless oil

Synthesis of compound 15
Compound 12 (0.18 g, 0.17 mmol) was deprotected according to general procedure Boc removal to

Synthesis of compound 16
Compound 13 (0.22 g, 0.20 mmol) was deprotected according to general procedure Boc removal to yield the desired product 16 as a white solid (

Synthesis of compound 18
To a solution of norspermidine 17 (0.50 g, 3.81 mmol) in ethanol (10 mL) was treated with acrylonitrile (0.60 g, 11.4 mmol, 3 equiv.) at 25 °C. The solution was stirred for a further 48 h. The solution was then concentrated in vacuo, and the crude material was purified over silica gel, (DCM: methanol; 9.9:0.1 to 9:1 v/v). After combining fractions and concentrating them, the desired product 8